ABSTRACT Alcohol Use Disorder (AUD) is a genetically influenced brain disease that is frequently comorbid with Attention- Deficit/Hyperactivity Disorder (ADHD), a neurodevelopmental disorder that arises in childhood and persists into adulthood in 30-45% of cases. The presence of one disorder significantly increases the likelihood of the other, and individuals with comorbid AUD/ADHD are a challenging clinical population. Both disorders are characterized by impairments in cognitive control, a process regulated in part by dopamine (DA) signaling in the prefrontal cortex (PFC). Psychostimulants, the most commonly prescribed medications for ADHD, elevate PFC DA tone and improve cognitive control. However, because psychostimulants also elevate striatal DA, they may potentiate alcohol?s rewarding and stimulating effects, and reduce its sedating effects, among individuals with comorbid AUD/ADHD. Non-stimulant medications have been tested in this population, but none has demonstrated effects on both AUD and ADHD symptoms. Tolcapone (TOLC), a brain-penetrant catechol-O-methyltransferase (COMT) inhibitor approved for the treatment of Parkinson?s disease, may more selectively potentiate cortical, but not striatal, DA release, and has shown promise in improving cognitive control and reducing drinking in animal models. TOLC?s effects may be influenced by a common single nucleotide polymorphism (SNP) in COMT that regulates COMT efficacy. Individuals who carry the val allele of the COMT val158met SNP, which has been associated with relatively higher COMT activity (and thus, lower PFC DA tone), may be more likely to benefit from TOLC treatment. Our preliminary data indicate that TOLC reduces drinking among non-treatment-seeking individuals with AUD, and does so to a greater extent among those with more ADHD symptoms and among COMT val-allele carriers. This project aims to evaluate TOLC as a pharmacogenetic probe for AUD/ADHD treatment, by testing its effects on neuroimaging and laboratory-based AUD/ADHD measures and on drinking in the natural environment. A group of unmedicated individuals with comorbid AUD/ADHD will be recruited, and a within-subjects, placebo- controlled, double-blind design will be used to test TOLC and placebo effects on three sets of outcomes: 1) brain activation associated with cognitive control, selective attention, and alcohol cue reactivity; 2) alcohol subjective effects and risky decision-making after consumption of a standard drink in the lab; and 3) drinking over six days in the natural environment. Additionally, an exploratory aim will evaluate whether COMT val158met genotype moderates TOLC effects on any of these outcomes. Achievement of these aims will potentially advance brain- penetrant COMT inhibitors as a new treatment option for individuals with comorbid AUD/ADHD.